The occupational cancer malignant mesothelioma is newly diagnosed in up to 3,000 persons per year in the US and most of these patients will die within 12 months of diagnosis regardless of treatment. Millions remain at risk in the US and the number at risk is expected to climb in developing nations where asbestos continues to be used, often without protection. In order to significantly impact this disease more needs to be known about the molecular mechanisms required for the initiation and maintenance of the malignant state in the mesothelial cell. Although a number of investigators have described increases in expression of some genes in mesothelioma cells, no oncogenes have been shown to have functional importance. Studies preliminary to this work show that a unique oncogene named CaSm, which is likely to transform cells through its role in RNA message destabilization, has high levels of expression of message and protein in virtually all mesothelioma cell lines and the majority of mesothelioma tumors examined. Further preliminary studies show that antisense CaSm inhibits growth of mesothelioma cells in vitro and in vivo. Antisense CaSm inhibition of growth is associated with cell-specific cell cycle alterations and increased expression of specific cell cycle-associated proteins. From this work we formed the hypothesis that: elevated CaSm expression plays a critical role in the development and maintenance of the malignant phenotype in asbestos-induced malignant mesothelioma To establish the role of CaSm expression in the malignant phenotype of mesothelioma cells, a series of loss of function and gain of function experiments will be performed using sense and antisense strategies, as well as small inhibitory RNAs. Important gain of function experiments will also be performed in vivo through the development of a transgenic mouse which will conditionally express CaSm in a tissue-specific manner. Focus will be placed upon the role of CaSm in regulation of expression of cell cycle proteins. Actinomycin chase and mutation analysis experiments will then be performed to determine if CaSm exerts its effect on cell cycle by destabilizing messages for these proteins. Finally experiments will determine whether asbestos specifically induces the expression of CaSm, and if it does so via reactive oxygen species or via other known mechanisms such as integrin adhesion. We believe these studies will provide exciting information and important insight into this cancer. [unreadable] [unreadable] [unreadable]